This invention relates to the composition, preparation and application of drug pre-loaded implant with desired structure and morphology containing anti-cancer agents and pertains to the treatment of cancer. The invented implants provided sustained release profiles after implantation. In this invention, we describe the composition, preparation of granular and disc implants containing doxorubicin. Homogeneous and heterogeneous drug delivery implants with hydroxyapatite and composite biocompatible materials are described. Fabrications of granular implants and disc implants are provided. Sustained release rate measurements of the doxorubicin as an example on the granular implant and the disc implant with a concentration of 0.02% by weight are also provided.
Today, drugs are frequently administered orally in liquid or tablet forms. To treat cancer, cytotoxic drugs are used with the object of selective destruction of cancer cells. The major disadvantages of this therapy are their toxic effects on normal cells, and the rapid clearance of the drug from cancerous tissues [Kato, T., in Controlled Drug Delivery, Vol. 11, Clinical Applications, ed. Bruck, S. D., CRC Press, Boca Raton, Fla., (1983) pp. 189-240]. To avoid problems incurred through the use of oral drugs, new dosage forms containing the drugs are introduced. There is a significant advantage to producing drug delivery systems that can maintain a constant drug release rate and can release the drug locally at the specific site of action. Therefore, implantable drug delivery systems were developed to optimize the therapeutic properties of the drug products and render them safer, more effective, and reliable. The advantages of drug delivery implants over conventional oral drugs are that:
1. a lower drug dose is needed,
2. the drug is protected from rapid in vivo metabolism,
3. the effectiveness of the drug at the site of the action is increased,
4. the patient compliance is increased and,
5. the delivery can continue over a period of time that can last for five years while requiring only minimum monitoring.
Methods of treating bone or cartilage cancer:
One of the important and effective drugs for treating osteosarcoma which is the most prevalent form of bone cancer is doxorubicin [Marsoni, S., Hoth, D., Simon, R., et al., Clinical Drug Development: An analysis of phase II trials, 1970-1985, Cancer Treat. Rep. 71, (1987) 71-80]. Since doxorubicin has poor oral absorption, it is administered intravenously. In the treatment of bone cancer, the problems associated with intravenous doxorubicin administration are: (i) toxicity of the drug; and, (ii) drug concentration at the cancerous site is likely to be very low because bones in general are moderately perfused organs. Administration of a 30 mg/m2 of doxorubicin as an intravenous bolus dose resulted to a marro drug concentration of 0.52 xcexcg/g, 2.5 hours after administration [Cohen, J. L., and Chan, K. K., in Bone Metastatsis Eds. Weiss, L. and Gilbert, H., A., Hall Medial Publishers, Boston, Mass., (1981) pp. 276-299]. Cardiotoxicity is the major chronic toxicity of doxorubicin and is dose-dependent [Sadee, W. and Torti, F. M. , in Fundamentals of Cancer Chemotherapy, eds. Hellmann, K. and Carter, S. K., McGraw-Hill, New York, N.Y., (1987) pp. 19-27]. A cumulative dose of 700 mg.m2 causes 30-40% of the patients to experience cardiotoxicity.
The treatment of bone cancer in most cases involves surgical intervention followed by systemic chemotherapy. This therapy, commonly referred to as adjuvant chemotherapy, is used to eradicate microscopic foci of metastatic disease. Ettiger et al. used a combination of doxorubicin and cisplatin as adjuvant therapy to treat osteosarcoma patients. Eighty percent of their patients were continuously disease-free for 23 months [Ettiger, L. J., Douglas, H. O., Higby, D. J., et al., Adjuvant adriamycin and cis-diammine-dichloro-platinum in promary osteosarcoma, Cancer 47, (1981) 248-254]. Rosen et al. developed a very unconventional but successful treatment protocol which involved the following sequential steps: (i) a regimen of systemic chemotherapy initiated several weeks before surgery; (ii) resection of enoprosthetic replacement of tumor-bearing bone rather than amputation; (iii) histologic examination of resected primary tumor to evaluate the effect of the preoperative chemotherapy; and, (iv) initiation of a new postoperative chemotherapeutic regimen, if preoperative chemotherapy regimen was not effective [Rosen, G., Capparros, B., Huvos, A. G., et al., Preoperative chemotherapy for osteogenicsarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy, Cancer, 49(1982) 1221-1230].
This mode of treatment showed that 93% of the patients had been continuously disease free for 20 months. However, the systemic toxicity of doxorubicin was a cause for concern in some patients.
The first objective of the present invention is to provide implants that can deliver drugs, proteins, peptides, DNA molecules, and hormones for treating bone or cartilage cancers. The second objective is to design the composition of the anti-cancer agents and the morphology of the biocompatible matrix materials to achieve the desired release rate profile for therapeutic treatment. The third objective is to provide methods for preparing of the foregoing implants.
As will become apparent, preferred features and characteristics of one aspect of the invention are applicable to any other aspects of the invention.
In one aspect, the invention provides a method for treating bone or cartilage cancer using hydroxyapatite drug delivery implants.
In a preferred embodiment, the drug delivery implant includes either a single-phase hydroxyapatite or multi-phase calcium phosphates. In another preferred embodiment, the hydroxyapatite can be amorphous or crystalline. In another preferred embodiment, the phase of the calcium phosphate can be alpha-tri-calcium phosphate or beta-tri-calcium phosphate. In other preferred embodiments, the drug delivery implant is composed with at least one biocompatible material such as biocompatible polymer, collagen, bioactive glass, calcium sulfate, carbonate apatite, fluoroapatite, or a biocompatible apatite phase.
In another preferred embodiment, homogeneous or heterogeneous implants are prepared by controlling the composition of anti-cancer agents, the biocompatible materials and the pressing process. In another preferred embodiment, the pressure applied to form the granular, disc, tablet, or block implants ranges from 0.1 to 40 MPa.
In another preferred embodiment, the invention includes using 0.02 weight percentage of doxorubicin to hydroxyapatite to obtain a sustained release.
In another preferred embodiment, the invention includes mixing doxorubicin and hydroxyapatite to form granular implants in a cylindrical shape. The diameter of the cylinder ranges from 5 microns to 10 millimeters.
In another preferred embodiment, the invention includes mixing doxorubicin and hydroxyapatite to form tablet or disc implants. The diameter of the tablet or disc ranges from 4 millimeters to 100 millimeters.
In another preferred embodiment, the invention essentially involves introducing granular and disc implants containing doxorubicin into the tumor or in its vicinity.